Publications by authors named "Su Young Kim"

418 Publications

Efficacy of venetoclax plus rituximab for relapsed CLL: Five-year follow-up of continuous or limited-duration therapy.

Blood 2021 Jun 3. Epub 2021 Jun 3.

Department of Hematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital; University of Melbourne, Australia.

We report long-term follow-up of the phase 1b study of venetoclax and rituximab (VenR) in patients with relapsed chronic lymphocytic leukemia (CLL), including outcomes with continuous or limited-duration therapy. Patients received venetoclax daily (200-600 mg) and rituximab over 6 months, then venetoclax monotherapy. Patients achieving complete response (CR), CR with incomplete marrow recovery (CRi), or undetectable minimal residual disease (uMRD) assessed by flow cytometry (<10-4 cutoff) were allowed, but not required, to discontinue therapy, while remaining on study and could be re-treated with VenR upon progression. Median follow-up for all patients (N=49) was 5.3 years. Five-year rates for overall survival, progression-free survival, and duration of response were 86% (95% CI, 72-94), 56% (40-70), and 58% (40-73), respectively. Of the 33 deep responders (CR/CRi or uMRD), 14 remained on venetoclax monotherapy (continuous therapy), and 19 stopped venetoclax therapy (limited-duration therapy) after a median of 1.4 years. Five-year estimates of ongoing response were similar between continuous (71% [95% CI, 39-88]) or limited-duration therapy (79% [49-93]). Six of 19 patients in the latter group had subsequent disease progression, all >2 years off venetoclax (range, 2.1-6.4). Four patients were re-treated with VenR, with partial responses observed in the 3 evaluable to date. VenR induced deep responses that were highly durable with either continuous or limited-duration therapy. Retreatment with VenR induced responses in patients with CLL progression after discontinuing therapy. Continuous exposure to venetoclax in deep responders does not appear to provide incremental benefit. ClinicalTrials.gov ID: NCT01682616.
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http://dx.doi.org/10.1182/blood.2020009578DOI Listing
June 2021

Long-term Follow-up of Patients with Relapsed or Refractory Non-Hodgkin Lymphoma Treated with Venetoclax in a Phase 1, First-in-Human Study.

Clin Cancer Res 2021 Jun 3. Epub 2021 Jun 3.

Haematology, Peter MacCallum Centre, Melbourne.

Purpose: We previously reported a 44% overall response rate (ORR) with venetoclax in a phase 1 study of relapsed/refractory NHL. Complete remission (CR) was observed in patients with mantle cell lymphoma ([MCL], 21%, n=6/28) and follicular lymphoma ([FL], 17%, n=5/29), and partial response (PR) noted in several patients with Waldenström macroglobulinemia (WM), and marginal zone lymphoma (MZL). Here, we report the long-term outcomes of these four cohorts.

Patients And Methods: All patients (n=106) received venetoclax monotherapy in dose cohorts of 200 - 1200 mg daily until disease progression or unacceptable toxicity. ORR, PFS, DoR, and adverse events (AEs) were evaluated.

Results: At median follow-up of 38.5 months (range: 30.0 - 46.5), median PFS for 106 patients was 5.4 (95% CI: 3.5 - 8.4) months (FL: 10.8; MCL: 11.3; MZL: 21.2; WM: 30.4). Median DoR was 14.9 (95% CI: 9.7 - 27.6) months (FL: 26.6; MCL: 15.7; MZL: 20.1; WM: 25.3). Achievement of CR vs. PR predicted longer DoR in both MCL (31.5 vs. 10.1 months) and FL (37.6 vs. 9.7 months). All grade hematologic AEs were infrequent: neutropenia (19%), anemia (17%), and thrombocytopenia (15%), with no new cytopenias {greater than or equal to}2 years on therapy. Non-hematological AEs included nausea (47%), diarrhea (43%), fatigue (40%), with decreased incidence {greater than or equal to}1 year.

Conclusions: Venetoclax monotherapy has a manageable safety profile and achieves durable responses in a subset of patients with FL, MCL, WM, and MZL, particularly in those who achieve CR. Further research is warranted on combination strategies to enhance the durability of response to venetoclax.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4842DOI Listing
June 2021

Usefulness of a Colonoscopy Cap with an External Grid for the Measurement of Small-Sized Colorectal Polyps: A Prospective Randomized Trial.

J Clin Med 2021 May 27;10(11). Epub 2021 May 27.

Department of Internal Medicine, Wonju College of Medicine, Yonsei University, Wonju 24626, Korea.

Accurate measurement of polyp size during colonoscopy is crucial. The usefulness of cap-assisted colonoscopy and external grid application on monitor (gCAP) was evaluated for polyp size measurement in this 3-year, single-center, single-blind, randomized trial. Using the endoscopic forceps width as reference, the discrepancy percent (DP), error rate (ER), and measurement time were compared between gCAP and visual estimation (VE) after randomization. ER was calculated within a 20% and 33% limit. From the 111 patients, 280 polyps were measured. The mean polyp sizes were 4.0 ± 1.7 mm and 4.2 ± 1.8 mm with gCAP and VE, respectively ( = 0.368). Compared with that by the forceps method, DP was significantly lower in the gCAP group than in the VE group. Moreover, ER was significantly lower in the gCAP group within its preset limit. The measurement time was 4 s longer in the gCAP group than in the VE group (8.2 ± 4.8 s vs. 4.2 ± 1.5 s; < 0.001). However, the forceps method lasted 28 s longer than the others. On subgroup analysis by size, gCAP was more accurate for polyp size ≥ 5 mm. The gCAP method was more accurate for polyp size measurement than VE, especially for polyps ≥ 5 mm, and was more convenient than the forceps method.
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http://dx.doi.org/10.3390/jcm10112365DOI Listing
May 2021

Colonoscopy Versus Fecal Immunochemical Test for Reducing Colorectal Cancer Risk: A Population-Based Case-Control Study.

Clin Transl Gastroenterol 2021 Apr 30;12(5):e00350. Epub 2021 Apr 30.

Center of Biomedical Data Science, Yonsei University Wonju College of Medicine, Wonju, Korea.

Introduction: Use of colonoscopy or the fecal immunochemical test (FIT) for colorectal cancer (CRC) prevention is supported by previous studies. However, there is little specific evidence regarding comparative effectiveness of colonoscopy or FIT for reducing CRC risk. In this study, we compared the association of CRC risk with colonoscopy and FIT using a nationwide database.

Methods: This population-based case-control study used colonoscopy and FIT claims data from the Korean National Health Insurance System from 2002 to 2013. Data were analyzed from 61,221 patients with newly diagnosed CRC (case group) and 306,099 individuals without CRC (control group). Multivariable logistic regression models were used to evaluate the association between CRC and colonoscopy or FIT.

Results: Colonoscopy was associated with a reduced subsequent CRC risk (adjusted odds ratio [OR] 0.29). Stronger associations were found between colonoscopy and distal CRC, compared with proximal CRC (0.24 vs 0.47). In an analysis stratified by sex, the association was weaker in female subjects compared with male subjects (0.33 vs 0.27). Any FIT exposure was associated with CRC risk with an OR of 0.74; this association was stronger for distal cancer. As the frequency of cumulative FIT assessments increased (from 1 to ≥5), the OR of FIT exposure for CRC gradually decreased from 0.81 to 0.45.

Discussion: The association of colonoscopy or FIT with reduced CRC risk was stronger for distal CRC than for proximal CRC. FIT showed less CRC risk reduction than colonoscopy. However, as the frequency of cumulative FIT assessments increased, the association with CRC prevention became stronger.
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http://dx.doi.org/10.14309/ctg.0000000000000350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088829PMC
April 2021

Activity of Oxazolidinone against Nontuberculous Mycobacteria, Including Macrolide-Resistant Clinical Isolates.

Antimicrob Agents Chemother 2021 Apr 26. Epub 2021 Apr 26.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

We evaluated the activities of oxazolidinone antibiotics including linezolid, sutezolid, and delpazolid against clinical nontuberculous mycobacteria isolates. Regardless of macrolide resistance, for , , and sutezolid showed the lowest minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) value among oxazolidinone antibiotics. However, for , , the MIC and MBC values for all oxazolidinone antibiotics showed similar values. Oxazolidinone antibiotics warrant further investigation as potential antibiotics.
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http://dx.doi.org/10.1128/AAC.02306-20DOI Listing
April 2021

Association between 16S rRNA gene mutations and susceptibility to amikacin in Mycobacterium avium Complex and Mycobacterium abscessus clinical isolates.

Sci Rep 2021 Mar 17;11(1):6108. Epub 2021 Mar 17.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-ro 81, Gangnam-gu, Seoul, 06351, South Korea.

We evaluated the association between 16S rRNA gene (rrs) mutations and susceptibility in clinical isolates of amikacin-resistant nontuberculous mycobacteria (NTM) in NTM-pulmonary disease (PD) patients. Susceptibility was retested for 134 amikacin-resistant isolates (minimum inhibitory concentration [MIC] ≥ 64 µg/ml) from 86 patients. Amikacin resistance was reconfirmed in 102 NTM isolates from 62 patients with either Mycobacterium avium complex-PD (MAC-PD) (n = 54) or M. abscessus-PD (n = 8). MICs and rrs mutations were evaluated for 318 single colonies from these isolates. For the 54 MAC-PD patients, rrs mutations were present in 34 isolates (63%), comprising all 31 isolates with amikacin MICs ≥ 128 µg/ml, but only three of 23 isolates with an MIC = 64 µg/ml. For the eight M. abscessus-PD patients, all amikacin-resistant (MIC ≥ 64 µg/ml) isolates had rrs mutations. In amikacin-resistant isolates, the A1408G mutation (n = 29) was most common. Two novel mutations, C1496T and T1498A, were also identified. The culture conversion rate did not differ by amikacin MIC. Overall, all high-level and 13% (3/23) of low-level amikacin-resistant MAC isolates had rrs mutations whereas mutations were present in all amikacin-resistant M. abscessus isolates. These findings are valuable for managing MAC- and M. abscessus-PD and suggest the importance of phenotypic and genotypic susceptibility testing.
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http://dx.doi.org/10.1038/s41598-021-85721-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969740PMC
March 2021

Activity of Rifamycin Derivatives against Nontuberculous Mycobacteria, including Macrolide-/Amikacin-Resistant Clinical Isolates.

Antimicrob Agents Chemother 2021 Mar 8. Epub 2021 Mar 8.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

We evaluated the activity of rifamycin derivatives, including rifampin, rifapentine, rifaximin, and rifabutin, against clinical nontuberculous mycobacteria (NTM) isolates. Of the rifamycin derivatives, rifabutin showed the lowest MICs against all NTM species, including complex, , and Rifabutin also had effective activity against macrolide- and aminoglycoside-resistant NTM isolates. Rifabutin could be worth considering as a therapeutic option for NTM disease, particularly drug-resistant disease.
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http://dx.doi.org/10.1128/AAC.02611-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092860PMC
March 2021

Genetic Analysis of Korean Adult Patients with Nontuberculous Mycobacteria Suspected of Primary Ciliary Dyskinesia Using Whole Exome Sequencing.

Yonsei Med J 2021 Mar;62(3):224-230

Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Purpose: Nontuberculous mycobacteria (NTM) is ubiquitous in the environment, but NTM lung disease (NTM-LD) is uncommon. Since exposure to NTM is inevitable, patients who develop NTM-LD are likely to have specific susceptibility factors, such as primary ciliary dyskinesia (PCD). PCD is a genetically heterogeneous disorder of motile cilia and is characterized by chronic respiratory tract infection, organ laterality defect, and infertility. In this study, we performed whole exome sequencing (WES) and investigated the genetic characteristics of adult NTM patients with suspected PCD.

Materials And Methods: WES was performed in 13 NTM-LD patients who were suspected of having PCD by clinical symptoms and/or ultrastructural ciliary defect observed by transmission electron microscopy. A total of 45 PCD-causing genes, 23 PCD-candidate genes, and 990 ciliome genes were analyzed.

Results: Four patients were found to have biallelic loss-of-function (LoF) variants in the following PCD-causing genes: , , , and . In four other patients, only one LoF variant was identified, while the remaining five patients did not have any LoF variants.

Conclusion: At least 30.8% of NTM-LD patients who were suspected of having PCD had biallelic LoF variants, and an additional 30.8% of patients had one LoF variant. Therefore, PCD should be considered in patients with NTM-LD with symptoms or signs suspicious of PCD.
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http://dx.doi.org/10.3349/ymj.2021.62.3.224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934102PMC
March 2021

Venetoclax and Navitoclax in Combination with Chemotherapy in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma.

Cancer Discov 2021 Jun 16;11(6):1440-1453. Epub 2021 Feb 16.

The University of Chicago Medicine, Chicago, Illinois.

Combining venetoclax, a selective BCL2 inhibitor, with low-dose navitoclax, a BCL-X/BCL2 inhibitor, may allow targeting of both BCL2 and BCL-X without dose-limiting thrombocytopenia associated with navitoclax monotherapy. The safety and preliminary efficacy of venetoclax with low-dose navitoclax and chemotherapy was assessed in this phase I dose-escalation study (NCT03181126) in pediatric and adult patients with relapsed/refractory (R/R) acute lymphoblastic leukemia or lymphoblastic lymphoma. Forty-seven patients received treatment. A recommended phase II dose of 50 mg navitoclax for adults and 25 mg for patients <45 kg with 400 mg adult-equivalent venetoclax was identified. Delayed hematopoietic recovery was the primary safety finding. The complete remission rate was 60%, including responses in patients who had previously received hematopoietic cell transplantation or immunotherapy. Thirteen patients (28%) proceeded to transplantation or CAR T-cell therapy on study. Venetoclax with navitoclax and chemotherapy was well tolerated and had promising efficacy in this heavily pretreated patient population. SIGNIFICANCE: In this phase I study, venetoclax with low-dose navitoclax and chemotherapy was well tolerated and had promising efficacy in patients with relapsed/refractory acute lymphoblastic leukemia or lymphoblastic lymphoma. Responses were observed in patients across histologic and genomic subtypes and in those who failed available therapies including stem cell transplant...
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http://dx.doi.org/10.1158/2159-8290.CD-20-1465DOI Listing
June 2021

Genome-wide association study in patients with pulmonary complex disease.

Eur Respir J 2021 Feb 4. Epub 2021 Feb 4.

Respiratory Disease Center, Fukujuji Hospital, Japan Anti-Tuberculosis Association, Tokyo, Japan.

Rationale: Nontuberculous mycobacteria (NTM) are environmental mycobacteria that can cause a chronic progressive lung disease. Although epidemiological data indicate potential genetic predisposition, its nature remains unclear.

Objectives: We aimed to identify host susceptibility loci for complex (MAC), the most common NTM pathogen.

Methods: This genome-wide association study (GWAS) was conducted in Japanese patients with pulmonary MAC and healthy controls, followed by genotyping of candidate single-nucleotide polymorphisms (SNPs) in another Japanese cohort. For verification by Korean and European ancestry, we performed SNP genotyping.

Results: The GWAS discovery set included 475 pulmonary MAC cases and 417 controls. Both GWAS and replication analysis of 591 pulmonary MAC cases and 718 controls revealed the strongest association with chromosome 16p21, particularly with rs109592 (p=1.64E-13, odds ratio=0.54), which is in an intronic region of the calcineurin like EF-hand protein 2 (). Expression quantitative trait loci analysis demonstrated an association with lung CHP2 expression. CHP2 was expressed in the lung tissue in pulmonary MAC disease. This SNP was associated with the nodular bronchiectasis subtype. This SNP was also significantly associated with the disease in patients of Korean (p=2.18E-12, odds ratio=0.54) and European (p=5.12E-03, odds ratio=0.63) ancestry.

Conclusions: We identified rs109592 in the locus as a susceptibility marker for pulmonary MAC disease.
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http://dx.doi.org/10.1183/13993003.02269-2019DOI Listing
February 2021

A Clofazimine-Containing Regimen Confers Improved Treatment Outcomes in Macrophages and in a Murine Model of Chronic Progressive Pulmonary Infection Caused by the Complex.

Front Microbiol 2020 14;11:626216. Epub 2021 Jan 14.

Department of Microbiology, Institute for Immunology and Immunological Disease, Brain Korea 21 Program for Leading Universities and Students (PLUS) Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.

Treatment outcomes using the standard regimen (a macrolide, ethambutol, and rifampicin) for complex-pulmonary disease (MAC-PD) remain unsatisfactory. Thus, improved treatment regimens for MAC-PD are required. Clofazimine has recently been revisited as an effective drug against mycobacterial infection. We performed a comparison between the standard regimen and an alternative regimen (replacing the rifampicin of the standard regimen with clofazimine) based on the intracellular anti-MAC activities of the individual drugs in a murine model of chronic progressive MAC-pulmonary infection (MAC-PI). The intracellular anti-MAC activities of the individual drugs and their combinations in murine bone marrow-derived macrophages (BMDMs) were determined. The treatment efficacies of the standard and clofazimine-containing regimens were evaluated in mice chronically infected with by initiating 2- and 4-week treatment at 8 weeks post-infection. Bacterial loads in the lung, spleen, and liver were assessed along with lung inflammation. Insufficient intracellular anti-MAC activity of rifampicin in BMDMs was recorded despite its low minimum inhibitory concentrations (MICs), whereas optimal intracellular killing activity against all tested MAC strains was achieved with clofazimine. Compared to the standard regimen, the clofazimine-containing regimen significantly reduced CFUs in all organs and achieved marked reductions in lung inflammation. The replacement of rifampicin with clofazimine in the treatment regimen resulted in more favorable outcomes in an animal model of chronic progressive MAC-PI. Intriguingly, 2 weeks of treatment with the clofazimine-containing regimen reduced bacterial loads more effectively than 4 weeks of treatment with the standard regimen in -infected mice. Thus, the clofazimine-containing regimen also had a treatment-shortening effect.
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http://dx.doi.org/10.3389/fmicb.2020.626216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841306PMC
January 2021

Corrigendum to "Nod 1, a CARD protein, enhances pro-interleukin-1 beta processing through the interaction with pro-caspase-1" [Biochem. Biophys. Res. Commun. 299(4) (2002) 652-8].

Biochem Biophys Res Commun 2021 Mar 29;543:97. Epub 2021 Jan 29.

Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea. Electronic address:

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http://dx.doi.org/10.1016/j.bbrc.2021.01.063DOI Listing
March 2021

Metabolic Engineering of Extremophilic Bacterium for the Production of the Novel Carotenoid Deinoxanthin.

Microorganisms 2020 Dec 25;9(1). Epub 2020 Dec 25.

School of Environmental Engineering, University of Seoul, Seoul 02504, Korea.

Deinoxanthin, a xanthophyll derived from species, is a unique organic compound that provides greater antioxidant effects compared to other carotenoids due to its superior scavenging activity against singlet oxygen and hydrogen peroxide. Therefore, it has attracted significant attention as a next-generation organic compound that has great potential as a natural ingredient in a food supplements. Although the microbial identification of deinoxanthin has been identified, mass production has not yet been achieved. Here, we report, for the first time, the development of an engineered extremophilic microorganism, strain R1, that is capable of producing deinoxanthin through rational metabolic engineering and process optimization. The genes and were first introduced into the genome to reinforce the metabolic flux towards deinoxanthin. The optimal temperature was then identified through a comparative analysis of the mRNA expression of the two genes, while the carbon source was further optimized to increase deinoxanthin production. The final engineered strain R1 was able to produce 394 ± 17.6 mg/L (102 ± 11.1 mg/g DCW) of deinoxanthin with a yield of 40.4 ± 1.2 mg/g sucrose and a productivity of 8.4 ± 0.2 mg/L/h from 10 g/L of sucrose. The final engineered strain and the strategies developed in the present study can act as the foundation for the industrial application of extremophilic microorganisms.
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http://dx.doi.org/10.3390/microorganisms9010044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823818PMC
December 2020

Phase 1/2 study of venetoclax, a BCL-2 inhibitor, in Japanese patients with relapsed or refractory chronic lymphocytic leukemia and small lymphocytic lymphoma.

Int J Hematol 2021 Mar 23;113(3):370-380. Epub 2020 Oct 23.

Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.

Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have limited treatment options. Venetoclax is a potent BCL-2 inhibitor that induces apoptosis in CLL cells. This open-label, phase 1/2 study (NCT02265731) evaluated the safety, pharmacokinetics, and efficacy of venetoclax in Japanese patients with R/R CLL/SLL. Patients enrolled in phase 1 received 400 mg/day venetoclax monotherapy. Patients enrolled in phase 2 received 400 mg/day venetoclax, plus rituximab. Venetoclax was administered with a weekly stepwise ramp-up in doses. In phase 2, efficacy was evaluated by objective response rate (ORR). Twelve patients were enrolled, six in each arm. The most common grade ≥ 3 adverse events were neutropenia (83%), lymphopenia (67%), leukopenia (33%), and thrombocytopenia (17%). Patients receiving venetoclax monotherapy achieved an ORR of 100%, including a complete remission (CR) rate of 17%. Patients receiving combination therapy had an ORR of 67% and a CR rate of 50%. The venetoclax pharmacokinetics profile in Japanese patients was similar to that of Western patients. Venetoclax 400 mg/day monotherapy or in combination with rituximab was well-tolerated and induced promising responses in Japanese patients with R/R CLL/SLL. Although patient numbers were small, the safety profile was largely consistent with other Western studies. Clinical trial registration: clinicaltrials.gov; NCT02265731.
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http://dx.doi.org/10.1007/s12185-020-03024-3DOI Listing
March 2021

Efficacy of iron supplementation in patients with inflammatory bowel disease treated with anti-tumor necrosis factor-alpha agents.

Therap Adv Gastroenterol 2020 23;13:1756284820961302. Epub 2020 Sep 23.

Department of Internal Medicine, Division of Gastroenterology, Gachon University, Gil Medical Center, 21, Namdong-daero 774beon-gil, Namdong-gu, Incheon, 21565, Korea.

Background: Anemia is a common extraintestinal manifestation of inflammatory bowel disease (IBD). However, data on the influence of anti-tumor necrosis factor-alpha (anti-TNF-α) agents and iron supplementation on anemia in patients with IBD are sparse. We assessed the effect of iron supplementation in patients with IBD initially treated with an anti-TNF-α agent.

Methods: Data from 79 IBD patients who started anti-TNF-α treatment at a tertiary hospital were analyzed. The patients were divided into the anti-TNF-α ( = 52) and anti-TNF-α with iron supplementation ( = 27) groups. Effects on laboratory parameters, the prevalence of anemia, and disease activity were evaluated at baseline (year 0) and 1 year later.

Results: The hemoglobin (Hb) level significantly increased between years 0 and 1 in both groups [12.0 ± 1.8-13.3 ± 2.0 g/dL in the anti-TNF-α group ( < 0.001) and 9.8 ± 2.4-11.7 ± 2.3 g/dL in the anti-TNF-α and iron supplementation group ( = 0.004)]. In a subgroup analysis of severely anemic patients with IBD, iron supplementation increased the magnitude of the improvement in Hb level (8.5 ± 1.5-11.4 ± 2.1 g/dL;  = 0.001) compared with the anti-TNF-α group (9.3 ± 0.8-11.4 ± 2.7 g/dL;  = 0.081). Disease activity was significantly improved in both groups at year 1 compared with year 0. Persistent anemia was significantly correlated with severe anemia at baseline ( = 0.017).

Conclusion: In anemic patients with IBD, anti-TNF-α agents led to clinically meaningful improvements in anemia independent of iron supplementation. Also, iron supplementation could be helpful in severely anemic patients with IBD.
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http://dx.doi.org/10.1177/1756284820961302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520924PMC
September 2020

Subspecies-specific sequence detection for differentiation of Mycobacterium abscessus complex.

Sci Rep 2020 10 2;10(1):16415. Epub 2020 Oct 2.

Institute of Medical Biology, Polish Academy of Sciences, ul. Lodowa 106, 93-232, Lodz, Poland.

Mycobacterium abscessus complex (MABC) is a taxonomic group of rapidly growing, nontuberculous mycobacteria that are found as etiologic agents of various types of infections. They are considered as emerging human pathogens. MABC consists of 3 subspecies-M. abscessus subsp. bolletti, M. abscessus subsp. massiliense and M. abscessus subsp. abscessus. Here we present a novel method for subspecies differentiation of M. abscessus named Subspecies-Specific Sequence Detection (SSSD). This method is based on the presence of signature sequences present within the genomes of each subspecies of MABC. We tested this method against a virtual database of 1505 genome sequences of MABC. Further, we detected signature sequences of MABC in 45 microbiological samples through DNA hybridization. SSSD showed high levels of sensitivity and specificity for differentiation of subspecies of MABC, comparable to those obtained by rpoB sequence typing.
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http://dx.doi.org/10.1038/s41598-020-73607-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532137PMC
October 2020

Is Gastroesophageal Reflux Disease Really a Risk Factor for Acute Myocardial Infarction?

Authors:
Su Young Kim

J Neurogastroenterol Motil 2020 09;26(4):421-422

Division of Gastroenterology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do, Korea.

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http://dx.doi.org/10.5056/jnm20192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547183PMC
September 2020

Venetoclax Plus Rituximab in Relapsed Chronic Lymphocytic Leukemia: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From the MURANO Phase III Study.

J Clin Oncol 2020 12 28;38(34):4042-4054. Epub 2020 Sep 28.

Royal Melbourne Hospital, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Victoria, Australia.

Purpose: In previous analyses of the MURANO study, fixed-duration venetoclax plus rituximab (VenR) resulted in improved progression-free survival (PFS) compared with bendamustine plus rituximab (BR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). At the 4-year follow-up, we report long-term outcomes, response to subsequent therapies, and the predictive value of molecular and genetic characteristics.

Patients And Methods: Patients with CLL were randomly assigned to 2 years of venetoclax (VenR for the first six cycles) or six cycles of BR. PFS, overall survival (OS), peripheral-blood minimal residual disease (MRD) status, genomic complexity (GC), and gene mutations were assessed.

Results: Of 389 patients, 194 were assigned to VenR and 195 to BR. Four-year PFS and OS rates were higher with VenR than BR, at 57.3% and 4.6% (hazard ratio [HR], 0.19; 95% CI, 0.14 to 0.25), and 85.3% and 66.8% (HR, 0.41; 95% CI, 0.26 to 0.65), respectively. Undetectable MRD (uMRD) at end of combination therapy (EOCT) was associated with superior PFS compared with low MRD positivity (HR, 0.50) and high MRD positivity (HR, 0.15). Patients in the VenR arm who received ibrutinib as their first therapy after progression (n = 12) had a reported response rate of 100% (10 of 10 evaluable patients); patients subsequently treated with a venetoclax-based regimen (n = 14) had a reported response rate of 55% (six of 11 evaluable patients). With VenR, the uMRD rate at end of treatment (EOT) was lower in patients with GC than in those without GC ( = .042); higher GC was associated with shorter PFS. Higher MRD positivity rates were seen with and mutations at EOCT and with , , , and mutations at EOT.

Conclusion: Efficacy benefits with fixed-duration VenR are sustained and particularly durable in patients who achieve uMRD. Salvage therapy with ibrutinib after VenR achieved high response rates. Genetic mutations and GC affected MRD rates and PFS.
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http://dx.doi.org/10.1200/JCO.20.00948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768340PMC
December 2020

A comparison of Bayesian to maximum likelihood estimation for latent growth models in the presence of a binary outcome.

Int J Behav Dev 2020 Sep 10;44(5):447-457. Epub 2020 Jan 10.

University of North Texas Health Science Center, USA.

Latent growth models (LGMs) are an application of structural equation modeling and frequently used in developmental and clinical research to analyze change over time in longitudinal outcomes. Maximum likelihood (ML), the most common approach for estimating LGMs, can fail to converge or may produce biased estimates in complex LGMs especially in studies with modest samples. Bayesian estimation is a logical alternative to ML for LGMs, but there is a lack of research providing guidance on when Bayesian estimation may be preferable to ML or vice versa. This study compared the performance of Bayesian versus ML estimators for LGMs by evaluating their accuracy via Monte Carlo (MC) simulations. For the MC study, longitudinal data sets were generated and estimated using LGM via both ML and Bayesian estimation with three different priors, and parameter recovery across the two estimators was evaluated to determine their relative performance. The findings suggest that ML estimation is a reasonable choice for most LGMs, unless it fails to converge, which can occur with limiting data situations (i.e., just a few time points, no covariate or outcome, modest sample sizes). When models do not converge using ML, we recommend Bayesian estimation with one caveat that the influence of the priors on estimation may have to be carefully examined, per recent recommendations on Bayesian modeling for applied researchers.
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http://dx.doi.org/10.1177/0165025419894730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497844PMC
September 2020

Long-term efficacy and safety of a new botulinum toxin type A preparation in mouse gastrocnemius muscle.

Toxicon 2020 Nov 10;187:163-170. Epub 2020 Sep 10.

Department of Dermatology, College of Medicine, Chung-Ang University, Seoul, 06974, South Korea; Department of Medicine, Graduate School, Chung-Ang University, Seoul, 06973, South Korea. Electronic address:

A new type A botulinum toxin (BoNT/A) preparation, JTM201 (NCBI chromosomal DNA ID: CP046450), has been developed, which comprises 900-kDa complexed toxin purified from Clostridium botulinum (strain: NCTC13319), but its safety and efficacy have not yet been evaluated. The purpose of this study was to evaluate the long-term efficacy and safety of JTM201 at different concentrations in comparison to another commercially available BoNT/A product, Botox® (onabotulinumtoxin A, ONA), using a mouse model. The LD of JTM201 was similar to that of ONA, but the intrinsic activity of JTM201 was higher than that of ONA. Functional recovery of the nerves and muscles in SKH-1 mice after administration of the two BoNT/A preparations (JTM201 and ONA) to the right gastrocnemius muscle was observed over 24 weeks. In addition, JTM201 did not induce any skin or muscle inflammatory response in 24 weeks. Paralysis induced by neurotransmitter blockade after JTM201 administration was comparable to that of ONA treatment. Both muscle weight and volume decreased in a concentration-dependent manner following JTM201 or ONA toxin injection until week 4. Reduced muscle fiber size due to atrophy and consequent fibrosis were detected following injection of JTM201 or ONA. Moreover, we assessed the extent of diffusion of JTM201 or ONA to the tibialis anterior and quadriceps femoris muscles, demonstrating limited diffusion to off-target muscles. In conclusion, JTM201 demonstrated long-term efficacy and safety equivalent to those of ONA based on compound muscle action potential, muscle volume, and histology analyses. These data suggest that JTM201 is a new BoNT/A formulation with safety and efficacy comparable to those of ONA.
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http://dx.doi.org/10.1016/j.toxicon.2020.09.003DOI Listing
November 2020

Protective behavioral strategies are more helpful for avoiding alcohol-related problems for college drinkers who drink less.

J Am Coll Health 2020 Sep 1:1-7. Epub 2020 Sep 1.

Department of Health Behavior and Health Systems, School of Public Health, University of North Texas Health Science Center, Fort Worth, Texas, USA.

Objective: To examine race, gender, and alcohol use level as moderators of the association between protective behavioral strategies (PBS) and alcohol-related problems. A sample of 12,011 participants who reported recent drinking (87.7% White, 61% Women) from Project INTEGRATE, a study that combined individual participant data (IPD) from 24 brief motivational intervention trials for college students. Hierarchical regressions were conducted to determine whether there was a moderated effect of PBS on alcohol problems across alcohol use levels, and whether the moderated protective effect of PBS by alcohol use differed by gender and race. The protective association between PBS and alcohol-related problems was greater for those who drank less. This moderated effect did not differ across men and women or across racial groups. College drinking prevention programs should ensure that students are aware of the limits of PBS as a mitigator of alcohol problems.
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http://dx.doi.org/10.1080/07448481.2020.1807555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917150PMC
September 2020

Best Eradication Strategy in the Era of Antibiotic Resistance.

Antibiotics (Basel) 2020 Jul 23;9(8). Epub 2020 Jul 23.

Divison of Gastroenterology, Department of Internal Medicine, Gachon University, Gil Medical Center, 21, Namdong-daero 774beon-gil, Namdong-gu, Incheon 21565, Korea.

Antibiotic resistance is the major reason for treatment failure, and the increasing frequency of antibiotic resistance is a challenge for clinicians. Resistance to clarithromycin and metronidazole is a particular problem. The standard triple therapy (proton pump inhibitor, amoxicillin, and clarithromycin) is no longer appropriate as the first-line treatment in most areas. Recent guidelines for the treatment of infection recommend a quadruple regimen (bismuth or non-bismuth) as the first-line therapy. This treatment strategy is effective for areas with high resistance to clarithromycin or metronidazole, but the resistance rate inevitably increases as a result of prolonged therapy with multiple antibiotics. Novel potassium-competitive acid blocker-based therapy may be effective, but the data are limited. Tailored therapy based on antimicrobial susceptibility test results is ideal. This review discussed the current important regimens for treatment and the optimum eradication strategy.
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http://dx.doi.org/10.3390/antibiotics9080436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459868PMC
July 2020

Paediatric Strategy Forum for medicinal product development for acute myeloid leukaemia in children and adolescents: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

Eur J Cancer 2020 09 17;136:116-129. Epub 2020 Jul 17.

FORMA Therapeutics, USA.

Purpose: The current standard-of-care for front-line therapy for acute myeloid leukaemia (AML) results in short-term and long-term toxicity, but still approximately 40% of children relapse. Therefore, there is a major need to accelerate the evaluation of innovative medicines, yet drug development continues to be adult-focused. Furthermore, the large number of competing agents in rare patient populations requires coordinated prioritisation, within the global regulatory framework and cooperative group initiatives.

Methods: The fourth multi-stakeholder Paediatric Strategy Forum focused on AML in children and adolescents.

Results: CD123 is a high priority target and the paediatric development should be accelerated as a proof-of-concept. Efforts must be coordinated, however, as there are a limited number of studies that can be delivered. Studies of FLT3 inhibitors in agreed paediatric investigation plans present challenges to be completed because they require enrolment of a larger number of patients than actually exist. A consensus was developed by industry and academia of optimised clinical trials. For AML with rare mutations that are more frequent in adolescents than in children, adult trials should enrol adolescents and when scientifically justified, efficacy data could be extrapolated. Methodologies and definitions of minimal residual disease need to be standardised internationally and validated as a new response criterion. Industry supported, academic sponsored platform trials could identify products to be further developed. The Leukaemia and Lymphoma Society PedAL/EUpAL initiative has the potential to be a major advance in the field.

Conclusion: These initiatives continue to accelerate drug development for children with AML and ultimately improve clinical outcomes.
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http://dx.doi.org/10.1016/j.ejca.2020.04.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789799PMC
September 2020

310 nm UV-LEDs attenuate imiquimod-induced psoriasis-like skin lesions in C57BL/6 mice and inhibit IL-22-induced STAT3 expression in HaCaT cells.

Photochem Photobiol Sci 2020 Aug 25;19(8):1009-1021. Epub 2020 Jun 25.

Department of Dermatology, Chung-Ang University College of Medicine, Seoul, Korea. and Department of Medicine, Graduate School, Chung-Ang University, Seoul, Korea.

Ultraviolet light-emitting diodes (UV-LEDs) are a novel light source for phototherapy. This study aimed to evaluate the therapeutic effects of UV-LEDs on psoriasis. Importantly, 310 nm UV-LEDs have not been studied in psoriasis in vitro and in vivo. Effects due to 310 nm UV-LED and 311 nm narrowband ultraviolet B (NBUVB) irradiation were compared for suppressing IL-22-induced activation of STAT3 expression using cell viability assay, western blotting, and immunocytochemistry. C57BL/6 mice were topically treated with imiquimod (IMQ) for 6 consecutive days and degenerative changes were observed. Test groups were irradiated with a 310 nm UV-LED and 311 nm NBUVB. Phenotypic observations, histopathological examinations, and ELISA were conducted with skin and blood samples. STAT3-dependent IL-22 signalling and effects in keratinocytes are negatively regulated by the 310 nm UV-LED, which significantly ameliorated IMQ-induced psoriasis-like dermatitis development and reduced Th17 cytokine levels (IL-17A, IL-22) in serum and dorsal skin. Histopathological findings showed decreases in epidermal thickness and inflammatory T-cell infiltration in the UV-LED-irradiated groups. Quantitative PCR confirmed a UV radiation energy-dependent decrease in IL-17A and IL-22 mRNA levels. The results demonstrated that UV-LEDs had anti-inflammatory and immunoregulatory effects. So, UV-LED phototherapy inhibits psoriasis development by suppressing STAT3 protein and inflammatory cytokines and could be useful in treating psoriasis.
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http://dx.doi.org/10.1039/c9pp00444kDOI Listing
August 2020

Predictive value of an early amplitude-integrated electroencephalogram for short-term neurologic outcomes in preterm infants.

Turk J Pediatr 2020 ;62(3):367-378

Department of Pediatrics, Pusan National University Children's Hospital, Pusan National University School of Medicine, Yangsan, Korea.

Background And Objectives: The aim of this study was to compare serial scores of amplitude-integrated electroencephalography (aEEG) in preterm infants with favorable neurologic outcome compared with those with unfavorable neurologic outcome and to evaluate whether aEEG in the early days of life has predictive value for short-term neurologic outcome in preterm infants.

Methods: This prospective observational study included infants born at ≤32 weeks of gestational age and ≤1,500 g of birth weight. On the basis of brain ultrasonography findings, the infants were divided into two groups (favorable and unfavorable outcome group) at 36 weeks of corrected age or at discharge. aEEG was performed at 12-14 h (day-1), 46-48 h (day-2), 70-72 h (day-3), and 1 week (day-7) of life. The aEEG recordings were analyzed using the criteria described by Burdjalov et al.23 and the serial scores of aEEG were compared between the two groups.

Results: Thirty five infants were enrolled and 18 infants and 17 infants were identified into both groups, respectively. Infants in the favorable outcome group showed high scores in almost all parameters and the score of all parameters increased over time. However, the scores of all components decreased in day-2 compared with those of day 1 in the unfavorable outcome group. The total score less than 3 of day-2 has predictive value of 70.6% of sensitivity and 72.2% of specificity for unfavorable outcome.

Conclusion: We found that aEEG is a useful predictor for short-term neurologic outcome in preterm infants.
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http://dx.doi.org/10.24953/turkjped.2020.03.003DOI Listing
January 2020

Bisphenol A in infant urine and baby-food samples among 9- to 15-month-olds.

Sci Total Environ 2019 Dec 9;697:133861. Epub 2019 Aug 9.

School of Public Health, Seoul National University, Seoul, Republic of Korea. Electronic address:

Diet is the predominant source of bisphenol A (BPA) intake, but limited data are available on BPA levels in the diet of younger infants. This study investigated BPA levels in baby-food and urine samples collected from young infants (under 2 years old). Samples of homemade baby food (n = 210) and urine (n = 187) were collected at 9, 12, and 15 months after birth from a panel of Korean infants (n = 173). BPA levels in urine and food were measured using HPLC-MS/MS and GC-MS, respectively. BPA was above the limit of detection (LOD) in 85.5-85.7% of the urine samples and 32.5-76.3% of the baby-food samples. The median levels of BPA were 0.45 ng/g wet weight (IQR: not detectable to 5.16 ng/g wet weight) in homemade baby food, 0.93 μg/L (IQR:
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http://dx.doi.org/10.1016/j.scitotenv.2019.133861DOI Listing
December 2019

Associations of exposure to phthalates and environmental phenols with gynecological disorders.

Reprod Toxicol 2020 08 28;95:19-28. Epub 2020 Apr 28.

School of Public Health, Seoul National University, Seoul, Republic of Korea. Electronic address:

Phthalates and environmental phenols might be associated with some benign diseases that have been found to be hormone-sensitive. Current knowledge on adverse effects of these chemicals among reproductive women is limited and often controversial. Therefore, the purpose of this study was to investigate the association between the urinary concentration of phthalates and environmental phenols and gynecological disorders from 512 women of reproductive age. The association between chemical concentration and disease in the control and case groups was statistically determined with the questionnaire survey data and measurements using the LC-MS/MS. The results have shown that DEHP metabolites, ethyl paraben and 3,4-DHB showed significant direct associations with leiomyoma and benign ovarian tumors (p < 0.05). We found statistically significant positive relationships between exposure to chemicals (some DEHP metabolites, DHB) and prevalence of gynecologic disorders (p < 0.05). Furthermore, the ORs for leiomyoma associated with these compounds in always user for personal care products (PCPs) was higher than those of sometimes user. High levels of urinary concentrations of these compounds such as DEHP metabolites and parabens and their metabolites showed significant associations with leiomyoma and benign ovarian tumors.
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http://dx.doi.org/10.1016/j.reprotox.2020.04.076DOI Listing
August 2020

Effects of the DNA repair inhibitors, cytosine arabinoside and 3-aminobenzamide, on the frequency of radiation-induced micronuclei, nuclear buds, and nucleoplasmic bridges.

Genes Genomics 2020 06 20;42(6):673-680. Epub 2020 Apr 20.

Department of Preventive Medicine, School of Medicine, Jeju National University, Jeju-si, 63243, Jeju Special Self-Governing Province, Korea.

Background: Micronuclei (MN), nuclear bud (NBud), and nucleoplasmic bridge (NPB) are suggested as biomarkers for radiation exposure; however, they have not been extensively studied to understand the underlying mechanisms responsible for their formation.

Objectives: To (1) validate NBud and NPB within the cytokinesis-blocked micronucleus (CBMN) assay as biomarkers for radiation exposure and (2) determine the effects of the DNA repair inhibitors, cytosine arabinoside (Ara C) and 3-aminobenzamide (3-AB) on radiation-induced MN, NBud, and NPB formation.

Methods: Human blood samples were irradiated with 0-3 Gy X-rays and subsequently treated with Ara C and 3-AB. CBMN and chromosome aberration assays were carried out to measure MN, NBud, and NPB and dicentric chromosomes, respectively.

Results: The frequency of radiation-induced MN, NBud, and NPB increased in a dose-dependent manner. The frequency of MN, NBud, and NPB was highly and positively correlated with the dicentric chromosome, a standard biomarker for biodosimetry (r > 0.98, p < 0.0001). Furthermore, Ara C increased the frequency of MN, NBud, and NPB, whereas 3-AB increased the frequency of MN and NPB, but not NBud. Further, the potentiating effect of Ara C on the frequency of MN, NBud, and NPB was greater than that of 3-AB.

Conclusion: Our results validate NBuds and NPBs as independent valuable markers of radiation exposure. Additionally, we suggest that different mechanisms are likely involved in the formation of NBuds and NPBs following X-irradiation; however, additional studies are warranted to better understand the contribution of distinct DNA repair pathways to the formation of radiation-induced damages.
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http://dx.doi.org/10.1007/s13258-020-00934-8DOI Listing
June 2020

Efficacy of repeat forward-view examination of the right-sided colon during colonoscopy: A prospective randomized controlled trial.

J Gastroenterol Hepatol 2020 Oct 20;35(10):1746-1752. Epub 2020 Apr 20.

Divison of Gastroenterology, Department of Internal Medicine, Gachon University, Gil Medical Center, Incheon, South Korea.

Background And Aim: Generally, colonoscopy is less effective for detecting colorectal adenomas in the right-sided colon compared with the distal colon. Repeat forward-view (RF) examination of the right-sided colon has been suggested to increase the adenoma detection rate (ADR). However, studies investigating the efficacy of RF examination are lacking. Thus, the aim of this study was to determine whether RF examination in the right-sided colon enhances right-sided ADR.

Methods: We performed a prospective, randomized controlled trial, including asymptomatic subjects who underwent screening colonoscopy. Subjects were randomized to the RF group, in which the right-sided colon was examined twice in the forward view, or to the standard forward-view (SF) group, in which the right-sided colon was examined once in the forward view. The primary outcome was the right-sided ADR on RF examination of the right-sided colon.

Results: A total of 640 subjects completed the study protocol (RF group, n = 320; SF group, n = 320). The right-sided ADR in the RF group was significantly higher than that in the SF group (17.5% vs 11.9%, respectively; P = 0.044). In the RF group, an additional 31 adenomas were found, resulting in an increased detection rate of adenomas of 38.3% compared with the first forward view. The ADR of the whole colon was similar between the groups.

Conclusions: In our prospective randomized controlled trial, RF examination of the right-sided colon, which can be easily performed in clinical practice, was associated with an increased rate of detection of right-sided ADR.
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http://dx.doi.org/10.1111/jgh.15064DOI Listing
October 2020

miRNA Expression Profiles and Potential as Biomarkers in Nontuberculous Mycobacterial Pulmonary Disease.

Sci Rep 2020 02 21;10(1):3178. Epub 2020 Feb 21.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.

Pulmonary disease (PD) due to nontuberculous mycobacteria (NTM) is increasing globally, but specific biomarkers for NTM-PD have not been established. As circulating miRNAs are promising biomarkers for various diseases, we investigated whether miRNAs have potential as NTM-PD biomarkers. Sera from 12 NTM-PD patients due to Mycobacterium avium, M. intracellulare, M. abscessus, or M. massiliense and three healthy controls were initially evaluated via small RNA sequencing. Multiple miRNAs showed significant differences in expression in patients compared to in healthy controls, with some expression differences unique to PD caused by a specific mycobacterial species. Notably, 14 miRNAs exhibited significant expression differences in PD associated with all four mycobacteria. Validation by quantitative reverse-transcription-PCR in an additional 40 patients with NTM-PD and 40 healthy controls confirmed that four differentially expressed miRNAs (hsa-miR-484, hsa-miR-584-5p, hsa-miR-625-3p, and hsa-miR-4732-5p) showed significantly higher serum expressions in NTM-PD patients than in controls. Receiver operating characteristic curve analysis of these four miRNAs supported the discriminative potential for NTM-PD and their combination provided an improved diagnostic value for NTM-PD. Furthermore, bioinformatics analysis revealed their 125 target genes, which were mostly associated with immune responses. Collectively, this study identified four miRNAs as potential biomarkers for NTM-PD and provided insight into NTM-PD pathophysiology.
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http://dx.doi.org/10.1038/s41598-020-60132-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035291PMC
February 2020